Rational Structural Diversification and Application of DalPhos Ligands for use in Challenging C-N Cross-Coupling Reactions

Abstract

Transition-metal catalyzed transformations have revolutionized modern chemical synthesis; the 2001, 2005, and 2010 Nobel prizes in Chemistry attest to their broad applicability in academia and industry. To this end, advances in transition metal catalysis are rooted in the development of ancillary ligands that are capable of supporting electronically and coordinatively unsaturated metal centers. The Pdcatalyzed cross-coupling of amines and (hetero)aryl (pseudo)halides (Buchwald- Hartwig amination), to afford synthetically useful arylamines, has benefitted greatly in this regard. The use of highly efficient P,N-phenylene (‘DalPhos’) ligands in challenging CN cross-coupling reactions (e.g. hydrazine and ammonia monoarylation), has recently been disclosed by the Stradiotto group. Herein, a Pd/Mor-DalPhos catalyst system has been exploited for the preparation of a diverse range of (hetero)aryl hydrazines, useful synthons for the synthesis of myriad heterocyclic scaffolds, including N-aryl pyrazolones. These compounds have been identified as a potent class of anti-aggregants that may prevent the formation of toxic A? oligomer species, serving as candidates for the treatment of Alzheimer’s Disease. Employing a tandem monoarylation/condensation protocol, 25 examples of structurally diverse Edaravone derivatives were afforded in good yield. Biological testing allowed for the identification of several compounds highly active toward inhibition of A?-40 and biotin-A?42 formation; their IC50 values were also determined. Given the literature precedent for improved catalyst activity arising from subtle changes to the ancillary ligand framework, rational structural diversification of Mor- DalPhos has been achieved in an effort to improve efficiency. Eight new DalPhos variants prepared in good to excellent yield, featuring substitution of the phenylenebackbone with electron-withdrawing and donating groups, thiomorpholino substitution, and two structural isomers where the phenylene-backbone has been replaced with pyridine. New variants were combined with [Pd(cinnamyl)Cl]2 to yield coordination complexes which may allow for a greater understanding of the catalytic cycle for BHA. Finally, new ligands were screened in a series of challenging C-X (X = N, C, O) cross-coupling reactions; a pyridine-bridged ligand variant displays unparalled activity in acetone arylation.